Betrixaban: A Novel Oral Anticoagulant With a New Niche

Abstract

Objective: To evaluate the efficacy, safety, and clinical implication of betrixaban for prophylaxis of venous thromboembolism (VTE) in patients with acute medical illness. Data Sources: A search for clinical trials was performed from January 2006 to January 2017 in English language using Clinicaltrials.gov and PubMed/MEDLINE. The following search terms were used: betrixaban, pharmacokinetics, pharmacology, and drug safety. Study Selection: The following limits were used to access the clinical trials: controlled clinical trial, randomized clinical trial, clinical trial, clinical trial phase II, and clinical trial phase III. The search was narrowed to include only humans. Data Extraction: The search criteria resulted in 6 clinical trials assessing the safety and efficacy of betrixaban. Additionally, references from publications assessing the safety and efficacy of betrixaban in atrial fibrillation, treatment and prevention of VTE, and extended duration VTE prophylaxis were assessed. Data Synthesis: Prior to 2017, no anticoagulant therapy had been approved for extended VTE prophylaxis in acutely ill medical patients. Betrixaban is the first direct oral anticoagulant approved for VTE prophylaxis in adult, acutely ill patients at risk for thromboembolisms. Based on the APEX trial, betrixaban 80 mg administered daily for 35 to 42 days was compared to enoxaparin administered daily for 6 to 14 days. In 7441 patients, fewer VTEs were seen in the betrixaban compared to enoxaparin with no significant difference in adverse reactions. Conclusion: Based on clinical trials, betrixaban appears to be safe and effective in preventing VTE in acutely ill patients who are at risk of developing VTE.

Introduction

Venous thromboembolism (VTE) is a health care risk associated with acutely ill patients. VTE cases include deep vein thrombosis (DVT) and pulmonary embolism (PE), both of which can lead to patient disability and death. The estimated incidence of VTE in the United States is 950 000 annual cases, and it is expected to double to 1.82 million by 2050.¹ The burden of VTE cases are not just seen in morbidity and mortality of patients but also on health care costs. The average cost of acute treatment of one VTE case ranges from $12 000 to $15 000, with an overall estimated annual cost of 7 to 10 billion dollars to health care systems.²

Acute medically ill patients are at an increased risk of developing VTEs due to pro-inflammatory markers triggered by their acute illness.³ While approximately 74% of patients develop VTEs in the outpatient setting, 50% of those patients had an attributable recent hospitalization.³ Acute illnesses such as active malignancies, respiratory diseases, heart failure, and acute coronary syndromes are associated with prolonged increases of inflammatory cytokines that can increase the risk of VTE even after a patient has been discharged.³ In observational studies of VTE incidence, 67% of VTE cases had recent hospitalization within 30 days of hospital discharge.⁴

Currently, the American College of Chest Physicians (ACCP) clinical practice guidelines recommends low-dose parenteral anticoagulant thromboprophylaxis for high-risk patients who are acutely ill (grade 1B). The ACCP does not recommend the use of thromboprophylaxis in an extended duration beyond the acute medical stay (grade 2B).⁵ The current parenteral anticoagulants’ efficacy in prevention of VTE during an extended duration do not outweigh the potential safety issues, such as major bleeding events, to warrant treatment after an acute medical stay.³

Betrixaban is the first direct oral anticoagulant (DOAC) approved for VTE prophylaxis in adult, acutely ill patients at risk for thromboembolisms. It is recommended for daily administration with treatment duration of 35 to 42 days and approved for extended duration.⁶ Betrixaban was approved by the Food and Drug Administration in June 2017 and is marketed under the trade name Bevyxxa. Betrixaban’s approved duration of treatment provides coverage for patients in the 30 day postdischarge window when VTE risk is still elevated. This article provides a review of the phase II and phase III trials that provided the evidence for betrixaban’s Food and Drug Administration approval for the extended duration VTE prophylaxis.

Data Source

A search for clinical trials was performed from January 2006 to January 2018 in English language using Clinicaltrials.gov and PubMed/MEDLINE, using the same strategy for both databases. The following MeSH terms were used: betrixaban, pharmacokinetics, pharmacology, and drug safety. To access the clinical trials, the following limits were used: controlled clinical trial, randomized clinical trial, clinical trial, clinical trial phase II, and clinical trial phase III. The search was narrowed to include only humans. Other animals and incomplete and nonclinical trials were excluded from the search results. The search criteria resulted in 6 relevant clinical trials that assessed the safety and efficacy of betrixaban. Additionally, references from publications assessing the safety and efficacy of betrixaban in atrial fibrillation (AF), treatment and prevention of VTE, and extended duration VTE prophylaxis were assessed.

Pharmacology and Pharmacokinetics

Betrixaban is a direct factor Xa inhibitor taken once daily by mouth. Absorption of betrixaban is rapid, and mean peak concentrations occur 3 to 4 hours after administration. It shows little variation in peak-to-trough concentrations over a 24-hour dosing interval. Betrixaban is predominantly excreted unchanged in bile.^7,8 Renal clearance is low with 11% of a dose being recovered in the urine.⁸ C_max and AUC were significantly lower (50%) when betrixaban was administered after a meal high in fat and caloric value. Betrixaban is a substrate for P-glycoprotein, an efflux protein, but it is not a substrate for major CYP enzymes.⁷ The pharmacodynamic half-life is 20 hours with minimal diurnal variation in drug concentrations.⁸

The pharmacokinetics and pharmacodynamics were studied in various clinical trials (see Table 1). EXPLORE-Xa trial is a phase II randomized trial that was open label to warfarin but blinded to betrixaban doses. The study sample size was 561 patients aged ≥18 years with a documented or current atrial fibrillation/atrial flutter along with ≥1 risk factor for stroke. Patients were randomized to betrixaban 40, 60, 80 mg orally, once daily, or warfarin with a target international normalized ratio (INR) of 2.0 to 3.0. Pharmacodynamic properties were assessed by measuring thrombin generation (TG), which helps assess the risk of bleeding versus thrombosis, along with plasma betrixaban concentrations and D-dimer concentrations. Based on blood samples taken throughout the study at ~13 hours after dosing, levels of TG were shown to decrease with increasing concentrations of betrixaban. Levels of TG seen with betrixaban concentrations between 12 and 30 ng/mL were similar to those seen with therapeutic warfarin doses (INR 2.0-3.0). The steady state geometric mean betrixaban plasma concentrations week 4 were 6, 9.6, and 12 ng/mL for betrixaban doses 40, 60, and 80 mg, respectively. Plasma D-dimer concentrations were retrieved after 12 weeks of treatment. There was a significant reduction in D-dimer levels in all patients on warfarin or betrixaban. There was no statistical significance found in the reduction of D-dimer levels between the 3 different betrixaban groups versus warfarin.⁷

Table 1.

Pharmacokinetic and Pharmacodynamic Properties of Anticoagulants^7,8.

	Betrixaban	Enoxaparin	Warfarin
Dosing interval	Once daily (every 24 hours)	Twice daily (every 12 hours)	Once daily (every 24 hours)
Route	Oral	Subcutaneous	Oral
Onset of action		3-5 hours	24-72 hours
Duration	~24 hours	~12 h (40 mg dose)	2-5 days
Absorption	Oral (rapid)	N/A (subcutaneous, 100% F)	Oral (rapid, complete)
Volume of distribution		4.3 L	0.14 L/kg
Protein binding (%)	60	None	99
Metabolism	Minimal renal and CYP450	Hepatic (desulfation and depolymerization)	Hepatic (primarily CYP2C9)
Half-life (hours)	20	4.5-7	20-60 (average: 40)
Time to peak plasma concentration (hours)	3-4	3-3.5	~4
Excretion	Primarily biliary (unchanged); <5% renal	Urine	Urine (92%) primarily as metabolites
Drug-drug interactions (requiring dose adjustment)	Strong P-gp inhibitors (ie, diltiazem, ketoconazole, amiodarone, quinidine)		CYP2C9, CYP1A2, and CYP3A4 inhibitors and inducers
	Not a substrate for CYP enzymes
Drug-food interactions	Cmax and AUC decreased by fatty food	None	Ethanol:
			Acute: ↓ metabolism, ↑ PT/INR
			Chronic: ↑ metabolism, ↓ PT/INR
			Foods rich in vitamin K: ↓ effect
			Vitamin E: may ↑ effect
			Cranberry juice: may ↑ effect
Reversal	None	60% to 80% with protamine sulfate; rVIIa can be considered	Vitamin K: Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated factor VII can be considered

Abbreviations: PT, prothrombin time; INR, international normalized ratio.

EXPERT is a randomized phase II, multicenter, parallel-group open label clinical trial that was blinded to betrixaban doses. The study sample size was 214 with patients aged 18 to 75 years weighing 50 to 120 kg that were undergoing elective primary unilateral total knee replacement. Patients were randomized to doses of either betrixaban 15 mg bid or 40 mg bid, or enoxaparin 30 mg SC bid within 6 hours of surgery completion. The EXPERT trial states “a BID dosing regimen was selected in order to mimic a possible future controlled-release formulation designed to further flatten the diurnal PK and PD profile.” Plasma drug concentrations were sampled and pharmacodynamics results were obtained at various intervals including at screening, 1 to 4 hours post administration of morning dose of study medication on day 2, on discharge, and preceding a mandatory venogram from days 10 to 14. Plasma samples were assessed for betrixaban for a range of 0.100 to 50.0 ng/mL (based on analysis of 0.1 mL plasma). Patients’ anticoagulation status was measured by TG inhibition assay, anti-Xa activity, activated partial thromboplastin time, prothrombin time, and INR. The results showed that steady-state was reached after the first few doses for all betrixaban groups. A dose- and concentration-dependent effect were seen with betrixaban and inhibition of TG. The betrixaban 15 mg group had similar anti-TG results as the enoxaparin group but less anti-Xa activity. The betrixaban 40 mg group had stronger anti-TG activity and similar anti-Xa activity compared with enoxaparin.⁷

Clinical Trials

Phase II Clinical Trials

The EXPERT trial was a multicenter, open-label, blinded-endpoint, randomized controlled trial that studied the effective and safe use of 2 oral betrixaban doses (15 mg and 40 mg) compared to subcutaneous enoxaparin (30 mg) for the prevention of VTE in patients undergoing unilateral total knee replacement. Both patients and physicians were blinded to the betrixaban dose but the study was open-label to enoxaparin (vs betrixaban). Patients within the study population came from 19 different sites within the United States and Canada. Both male and female patients were included if they were between 18 and 75 years of age, weighing between 50 and 120 kg, and scheduled to undergo voluntary primary unilateral total knee replacement. Female patients were required to have no reproductive potential (ie, postmenopausal at least 2 years or status-post hysterectomy). Patients were screened for eligibility 1 to 30 days prior to undergoing surgery. Patients were excluded if they had any bleeding disorders, high bleeding risk, or a recent internal bleed; platelet count <100 000/mm³, hemoglobin <10 g/dL, or hematocrit <30%. Use of thrombolytics and anticoagulants was prohibited within the 7 days prior to surgery as well as during treatment. Eligible patients were randomized within the 6 hours following surgery in a 2:2:1 ratio to either betrixaban 15 mg orally (n = 88), betrixaban 40 mg orally (n = 84), or enoxaparin 30 mg subcutaneously (n = 43), respectively. Patients selected to receive betrixaban (either dose) had the initial dose administered 6 to 8 hours following surgery and then twice daily thereafter. Patients selected to receive enoxaparin had the initial dose administered 12 to 24 hours following surgery and then every 12 hours thereafter. All patients were treated for 10 to 14 days (unless prespecified stopping criteria were met). After being discharged from the hospital, patients administered the medication themselves. Between days 10 and 14, patients were scheduled to undergo mandatory venography (operated leg) and took their last dose of the study medication that same morning. Follow-up occurred every 2 to 4 days (either in person or by phone) until the patient stopped taking the medication. Another follow-up occurred 4 to 8 weeks after surgery. Both efficacy and safety endpoint analyses were reviewed by a blinded central adjudication committee (see Table 2).⁸

Table 2.

Phase II and Phase III Clinical Trials of Betrixaban^7-9.

Clinical Trial	Indication	Design	Inclusion Criteria	Intervention Doses	Primary Outcome Measures	Results
EXPERT Trial (Phase II)	VTE prevention following unilateral TKR	Open-label ENOX vs blinded BE, parallel, multicenter RCT (N = 214)	Male or female (18-75 years); weight 50-120 kg; undergoing elective primary unilateral TKR; females required to have no reproductive potential	BE15 and BE40 6-8 hours after surgery and BID thereafter; or ENOX30 SC 12-24 hours after surgery and BID thereafter	Efficacy: occurrence of VTE up to days 10-14	Efficacy: BE15 20% (95% CI = 11.4-31.3), BE40 15.4% (95% CI = 7.6-26.5), ENOX30 10% (95% CI = 2.8-23.7)
					Safety: major and CRNM bleeds	Safety: BE15 0% (95% CI = 0-4.2), BE40 2.4% (95% CI = 0.3-8.3); ENOX30 7% (95% CI = 1.5-19.1)
EXPLORE-Xa Trial (Phase II)	Stroke prevention in AF	Open-label warfarin vs double-blind BE, dose-ranging, multicenter RCT (N = 561)	Male or female (≥18 years), in AF or atrial flutter at time of enrolment or documented within previous year; and with 1 or more risk factors for stroke; INR ≤2.2 if on warfarin	BE40, BE60, BE80 orally once daily, or warfarin (target INR 2.0-3.0)	Occurrence of major or CRNM bleeding	Major or CRNM bleeds: BE40 vs warfarin, P = .04 (HR [95% CI = 0.017-1.135]), BE60 vs warfarin, P = .01 (HR [95% CI = 0.225-2.243]), BE80 vs warfarin, P = .02 (HR [95% CI = 0.239-2.389])
APEX Trial (Phase III)	Extended VTE prophylaxis in acutely ill medical patients with high VTE risk	Double-blind, double-dummy, parallel, multicenter, multinational RCT (N = 6850, planned)	Patients ≥40 years, hospitalized (<96 hours) for specified acute medical illness, restricted mobility, and have increased VTE risk (age ≥75 years, baseline D-dimer ≥2× ULN, or 2 additional ancillary risk factors for VTE)	BE80 orally once daily for 35-42 days, or ENOX40 for 6-14 days followed by placebo	Efficacy: composite of asymptomatic proximal DVT, symptomatic DVT, nonfatal PE, or VTE-related death through day 35	Cohort 1: BE80 6.9%, ENOX40 8.5% (RR = 0.81; 95% CI = 0.65-1.00; P = .054)
					Safety: occurrence of major bleeding	Cohort 2: BE80 5.6%, ENOX40 7.1% (RR = 0.80; 95% CI = 0.66-0.98; P = .03)
						Overall population: BE80 5.3%, ENOX40 7.0% (RR = 0.76; 95% CI = 0.63-0.92; P = .006)

Abbreviations: VTE, venous thromboembolism; TKR, total knee replacement; RCT, randomized controlled trial; BE, betrixaban; BE15, betrixaban 15 mg; BE40, betrixaban 40 mg; BE60, betrixaban 60 mg; BE80, betrixaban 80 mg; ENOX30, enoxaparin 30 mg; ENOX40, enoxaparin 40 mg; CRNM, clinically relevant nonmajor; HR, hazard ratio; CI, confidence interval; AF, atrial fibrillation; INR, international normalized ratio; DVT, deep vein thrombosis; PE, pulmonary embolism; BID, twice daily; SC, subcutaneously; ULN, upper limit of normal; hx, history.

The primary efficacy endpoint was incidence of VTE up to days 10 to 14, a composite of DVT (on mandatory venography of the operated leg), symptomatic proximal DVT, or PE. DVT was only diagnosed by venography if defects were detected on 2 images. VTE was also reported if it occurred between the time of venography and 4 to 8 weeks after surgery. Efficacy analyses were conducted only in patients with adjudicated evaluable venography or adjudicated confirmatory investigations for symptomatic DVT and/or PE. Overall, 82% of patients were qualified to undergo primary efficacy analyses. The primary efficacy endpoint was observed in 14/70 patients (20%) with betrixaban 15 mg (95% confidence interval [CI] = 11.4-31.3); in 10/65 patients (15.4%) with betrixaban 40 mg (95% CI = 7.6-26.5), and in 4/40 patients (10%) with enoxaparin (95% CI = 2.8-23.7). In all 3 groups, the majority of these events were asymptomatic DVTs. The confidence intervals of all 3 groups showed considerable overlap. Therefore, no conclusions could be drawn regarding a dose response.⁸

The primary safety endpoint was occurrence of overt bleeding events (major and clinically relevant nonmajor bleeds). A major bleed was defined as one that was fatal, involving a vital organ, requiring surgery/procedure, or a bleeding index ≥2.0. Bleeding index was defined as the amount of units of packed red blood cells or whole blood transfused to the patient plus the hemoglobin values before the bleeding episode minus the hemoglobin levels after the bleeding had been stabilized. Safety analyses were conducted only in patients who received at least one dose. Clinically relevant bleeding rates were observed in 0 patients with betrixaban 15 mg (95% CI = 0-4.2), in 2/84 patients (2.4%) with betrixaban 40 mg (95% CI = 0.3-8.3), and in 3/43 patients (7%) with enoxaparin (95% CI = 1.5-19.1). One patient in the enoxaparin group experienced a major bleed at the surgical site, while no major bleeds were reported in either of the betrixaban groups. Two patients in the enoxaparin group and 2 patients in the betrixaban 40 mg group experienced a clinically significant nonmajor bleed. Zero deaths occurred during the study and few patients reported any serious adverse events.⁸

The authors concluded that betrixaban has antithrombotic activity and is well tolerated at the doses tested in the study. Limitations of this trial included a smaller sample size in the enoxaparin group compared to the betrixaban group, as well as the decision to perform unilateral venography on the operated leg rather than bilateral venography, both likely contributing to the lower rate of VTE in the enoxaparin group. Furthermore, larger trials need to be conducted in order to draw conclusions regarding the more favorable dose for betrixaban for which the benefits outweigh the risks.⁸

The EXPLORE-Xa trial is a phase II clinical trial with patients aged ≥18 years, male or female with documented or current nonvalvular AF. They had to have at least one risk factor for stroke to be a candidate for anticoagulation with warfarin. Patients on warfarin had to have an INR of <2.2. Patients excluded were those who weighed <40 kg, were undergoing hemodialysis or peritoneal dialysis, had reversible AF, persistent uncontrolled hypertension, history of bleeding disorders or high risk of bleeding, and patients on verapamil. The primary outcome was time to occurrence of major (bleeding that reduced hemoglobin >20 g/L) or clinically relevant nonmajor (CRNM) bleeding. Clinically relevant nonmajor bleeding was defined as overt bleeding associated with medical intervention, temporary interruption of treatment, or patient discomfort. The secondary outcomes were any bleeding and time to occurrence of death, stroke (ischemic or nonischemic), or any systemic embolism. Patients were randomized (1:1:1:1 allocation) to betrixaban 40, 60, or 90 mg orally once a day or warfarin with a target INR of 2.0 or 3.0. Randomization was also done to balance patients by country (the United States, Canada, and Germany) and concomitant medications. There was no blinding between betrixaban and warfarin but the betrixaban dose was double blinded. Patients were to take betrixaban at bedtime and ancillary medications were allowed if necessary (such as aspirin). A total of 561 patients were screened and 508 were randomized to the 4 different treatment arms. All patients received at least one dose of study medications with similar rates of dropouts among the 4 groups. There were 127 patients enrolled from Canada, 369 from the United States, and 12 from Germany. Baseline characteristics were somewhat balanced, most patients above 70 years old, and most patients being male and Caucasian. Only 13% of patients were warfarin naïve. A total of 53.5% of patients had a glomerular filtration rate (GFR) of >70 mL/min and 8.1% of patients had a GFR <40 mL/min. The average CHADS₂ score was 2.2. Additional antiplatelet therapy was used in 39% to 42% of patients in each group. Compliance to betrixaban was at least 96% across all groups. The study duration was 11 months.⁷

The numbers of patients with a major or CRNM bleed were 1, 5, 5, 7 (betrixaban 40, 60, 80 mg, and warfarin, respectively). The rates of the primary outcome were lowest with betrixaban 40 mg (hazard ratio [HR] compared with warfarin = 0.14, P = .04; 95% CI = 0.017-1.135). Betrixaban 60 mg and 80 mg had rates of the primary outcome similar to warfarin. The outcome of any bleeding event occurred in 22, 32, 24, and 40 patients on betrixaban 40, 60, 80 mg, and warfarin, respectively. With betrixaban 40 mg and betrixaban 80 mg per day, the rates of any bleeding were reduced compared with warfarin (P values of .01 and .02 [unadjusted for multiple testing], respectively). All betrixaban groups suppressed D-dimer and thrombin generation, but only the 80 mg group had TG suppression similar to warfarin (see section “Pharmacology and Pharmacokinetics” for further details). One patient had died on betrixaban 40 mg and another had died on warfarin. A total of 2 patients suffered a stroke. One patient suffered a stroke on betrixaban 60 mg, and another patient suffered a stroke on betrixaban 80 mg. Both patients suffered an ischemic stroke. None of the patients experienced a myocardial infarction, systemic embolic event, or PE during the study. The occurrence of adverse events in the 4 treatment arms (9.4%, 9.4%, 8.7%, 9.4%) were similar while on betrixaban 40 mg, 60 mg, 80 mg, and warfarin. The number of patients who experienced diarrhea in the pooled betrixaban group (6.0%) was significantly higher when compared to warfarin (0.8%). Patients who had to discontinue early were more commonly seen in those taking betrixaban (8.9%) and less common in patients taking warfarin (6.3%). Each patient’s liver function tests were measured at each visit. The number of patients with an elevated alanine transaminase (ALT) greater than 3 times the upper limit of normal were higher with betrixaban (1.8%) than warfarin (0.8%). A dose-related increase was absent in these numbers with 3 (2.4%), 3 (2.4%), and 1 (0.8%) cases in the 40, 60, and 80 mg betrixaban groups, respectively.⁷

The EXPLORE-Xa trial explored the safety, efficacy, and tolerability of betrixaban compared with warfarin in patients with AF. This study was beneficial in comparison to other trials as it allowed patients with renal insufficiency (GFR < 40) as long as they were not on dialysis. The study was able to show that all 3 betrixaban groups had lower rates of the primary outcome (major or CRNM bleeds). This study indicates that betrixaban may have similar TG suppression activity to warfarin but with fewer bleeding events. Limitations of this study included the smaller sample size that limited the diversity in patients’ race and gender. P values were not provided for the baseline characteristics. There were 52 dropouts; however, the reason for dropouts were not adequately discussed. The study was funded by Portola Pharmaceuticals, and other pharmaceutical companies were also listed as conflicts of interest.⁷

Phase III Clinical Trial

Prior to 2017, no anticoagulant therapy had been approved for extended VTE prophylaxis in acutely ill medical patients. The risk for VTE in these patients is prolonged for at least the first month following hospital discharge. The APEX trial was a prospective, double-blind, double-dummy, parallel, multicenter, multinational, randomized controlled trial that studied and assessed the efficacy and safety of oral betrixaban for extended VTE prophylaxis in acutely ill medical patients with a specified acute medical illness (heart failure, respiratory failure, rheumatic disease, infectious disease, ischemic stroke). Both male and female patients were included if they were at least 40 years old, hospitalized (<96 hours) for a specified acute medical illness (as defined above), had limited mobility and specific VTE risk factors. Women were excluded if they were pregnant or breastfeeding. Patients were also excluded if they were hospitalized for more than 96 hours prior to undergoing randomization; NPO (nil per os; nothing through the mouth); had increased bleeding risk; a clinically significant bleed that occurred within the preceding 6 months; any previous significant gastrointestinal, pulmonary, or urogenital bleed, chronic peptic ulcer disease or gastritis; any comorbidity that will likely require major surgery or invasive procedure in the upcoming 3 months; any known intracranial lesions; major or ophthalmic surgery, biopsy of parenchymal organ, or serious trauma in the previous 3 months; active lung cancer or known history of bronchiectasis; end-stage renal disease (creatinine clearance [CrCl] <15 mL/min or on dialysis); prior or concurrent intracranial bleed; prior severe head trauma or any trauma in the previous 3 months; severe renal dysfunction and required use of a strong P-gp inhibitor; contraindications to anticoagulants; aspartate transaminase (AST)/ALT >3× ULN or alkaline phosphatase >2× ULN (upper limit of normal), active liver disease or cirrhosis, uncontrolled HIV; concurrent or history of alcohol or drug abuse within the previous 1 year; shock requiring vasopressors or unresponsive to fluid replacement; and any history of hypersensitivity reaction to study medications. A total of 7513 patients were randomized. Patients were randomized using an interactive voice-response system to 1 of 2 groups—the enoxaparin group or the betrixaban group. In the enoxaparin group, 3754 patients were assigned to receive enoxaparin 40 mg once a day administered subcutaneously for a duration of 6 to 14 days plus betrixaban placebo once a day by mouth for a duration of 35 to 42 days. In the betrixaban group, 3759 patients were assigned to receive betrixaban by mouth at an initial loading dose of 160 mg (two 80 mg tablets) followed by 80 mg once a day for a duration of 35 to 42 days plus enoxaparin placebo administered subcutaneously once a day for a duration of 6 to 14 days. The betrixaban dose was reduced to 40 mg once a day for patients who were also taking a concomitant strong P-gp inhibitor (ie, amiodarone, quinidine, verapamil). Additionally, all doses were reduced by 50% for patients with severe renal dysfunction (CrCl ≥15 mL/min and <30 mL/min); enoxaparin was reduced to 20 mg dose for really compromised patients Among all clinical trials designed to study extended VTE prophylaxis in acutely medically ill patients, APEX represents the only trial among these to include patients with severe renal dysfunction.⁹

The primary efficacy endpoint was a composite of asymptomatic proximal DVT (between days 32 and 47; detected by mandatory ultrasound), symptomatic proximal or distal DVT, symptomatic nonfatal PE, or death caused by VTE between days 1 and 42. Key secondary endpoints were symptomatic VTE, all components of the composite primary efficacy endpoint with death being from any cause rather than only death from VTE, and net clinical benefit. The primary safety endpoint was the incidence of major or clinically relevant nonmajor bleeds (until 7 days after discontinuing all study medications). Major bleeds were defined as a decrease in hemoglobin ≥2 g/dL, requiring ≥2 units of blood for transfusion, critical-site bleeding, or any bleed resulting in death.⁹

Two cohorts were established within the overall study population in order to analyze the primary outcome in a hierarchical fashion. This hierarchical sequence was meant to adjust for the type I error rate. Cohort 1 included patients with a baseline D-dimer elevated to >2× the upper limit of normal. Cohort 2 included all patients in cohort 1 plus patients ≥75 years old. Cohort 3 included the overall population within the study. The reason for this style of testing is that both a higher VTE risk and a greater benefit of prolonged VTE prophylaxis are expected in patients with elevated baseline D-dimer level or ≥75 years old. If superiority of betrixaban (with respect to the primary composite outcome) had been established in cohort 1 at an α level of .05, then the trial would have met its primary outcome and superiority would be tested in cohort 2. If superiority of betrixaban was met in cohort 2, then superiority would have been tested in the overall study population. Plans for statistical analysis specified that if superiority of betrixaban was not met in any between-group analyses, then all other analyses would be considered exploratory. All statistical tests were 2-sided with a type I error rate of 5.0%; 2-sided 95% confidence intervals were calculated.⁹

Efficacy analyses were only conducted in patients who received at least one dose and were appropriately assessed for VTE. A Cochran-Mantel-Haenszel model was used to determine the risk ratio for all efficacy analyses. In cohort 1, the primary efficacy endpoint occurred in 132 out of 1914 patients (6.9%) with betrixaban and in 166 out of 1956 patients (8.5%) with enoxaparin (relative risk [RR] = 0.81; 95% CI = 0.65-1.00; P = .054). Since statistical significance was not met in cohort 1, all other analyses were considered exploratory and no conclusions were drawn regarding statistical significance. In cohort 2, the primary efficacy endpoint occurred in 160 out of 2842 patients (5.6%) with betrixaban and in 204 out of 2893 patients (7.1%) with enoxaparin (RR = 0.80; 95% CI = 0.66-0.98; P = .03). In the overall population, the primary efficacy endpoint occurred in 165 out of 3112 patients (5.3%) with betrixaban and in 223 out of 3174 patients (7.0%) with enoxaparin (RR = 0.76; 95% CI = 0.63-0.92; P = .006). In the overall population, the first secondary efficacy endpoint (symptomatic VTE) occurred in 35 out of 3721 patients (0.9%) with betrixaban and in 54 out of 3720 patients (1.5%) with enoxaparin (RR = 0.64; 95% CI = 0.42-0.98; P = .04); the second secondary efficacy endpoint (primary efficacy endpoint + death from any cause) occurred in 298 out of 3245 patients (9.2%) with betrixaban and in 359 out of 3310 patients (10.8%) with enoxaparin (RR = 0.85; 95% CI = 0.75-1.05; P = .16); the net clinical benefit (composite of any component of the primary efficacy endpoint + primary safety endpoint) occurred in 179 out of 3112 patients (5.8%) with betrixaban and in 233 out of 3174 patients (7.3%) with enoxaparin (RR = 0.78; 95% CI = 0.65-0.95; P = .01). Results for the primary and key secondary efficacy outcome analyses are summarized in Table 3.⁹

Table 3.

Primary and Secondary Efficacy Endpoints of APEX Trial⁹.

	Cohort 1 (D-Dimer ≥2× ULN)				Cohort 2 (D-Dimer ≥2× ULN + ≥75 years old)				Cohort 3 (Overall Study Population)
	BE (%)	ENOX (%)	RR (95% CI)	P Value	BE (%)	ENOX (%)	RR (95% CI)	P Value	BE (%)	ENOX (%)	RR (95% CI)	P Value
Primary outcome
Primary composite efficacy outcome	6.9	8.5	0.81 (0.65-1.00)	.054	5.6	7.1	0.80 (0.66-0.98)	.03	5.3	7.0	0.76 (0.63-0.92)	.006
Key secondary outcomes
Symptomatic VTE	1.3	1.9	0.67 (0.42-1.07)	.09	1.0	1.4	0.71 (0.46-1.09)	0.11	.9	1.5	0.64 (0.42-0.98)	.04
Primary composite efficacy outcome + death from any cause	11.5	12.9	0.89 (0.75-1.05)	.16	9.8	10.9	0.90 (0.77-1.04)	.15	9.2	10.8	0.85 (0.73-0.98)	.02
Net clinical benefit	7.4	8.9	0.82 (0.66-1.01)	.07	6.1	7.4	0.82 (0.68-1.00)	.05	5.8	7.3	0.78 (0.65-0.95)	.01

Abbreviations: BE, betrixaban; ENOX, enoxaparin; RR, relative risk; CI, confidence interval; VTE, venous thromboembolism; ULN, upper limit of normal.

Safety analyses were only conducted in patients who received at least one dose. In cohort 1, major bleeding was observed in 0.6% with betrixaban and 0.7% with enoxaparin (RR = 0.88; 95% CI = 0.44-1.76; P = .72); major or clinically relevant nonmajor bleeding occurred in 3.1% with betrixaban and 1.9% with enoxaparin (RR = 1.64; 95% CI = 1.13-2.37; P = .009). In cohort 2, major bleeding was observed in 0.7% with betrixaban and 0.6% with enoxaparin (RR = 1.19; 95% CI = 0.66-2.11; P = .56); major or clinically relevant nonmajor bleeding occurred in 3.2% with betrixaban and 1.7% with enoxaparin (RR = 1.89; 95% CI = 1.38-2.59; P < .001). In the overall population, major bleeding was observed in 0.7% with betrixaban and 0.6% with enoxaparin (RR = 1.19; 95% CI = 0.67-2.12; P = .55); major or clinically relevant nonmajor bleeding occurred in 3.1% with betrixaban and 1.6% with enoxaparin (RR = 1.97; 95% CI = 1.44-2.68; P < .001). Results for the primary safety outcome analyses are summarized in Table 4. One patient in the betrixaban group experienced intracranial bleeding compared to 7 patients in the enoxaparin group. One death due to fatal bleeding occurred in each group.⁹

Table 4.

Primary Safety Endpoints of APEX Trial⁹.

	Cohort 1 (D-Dimer ≥2× ULN)				Cohort 2 (D-Dimer ≥2× ULN + ≥75 years old)				Cohort 3 (Overall Study Population)
	BE (%)	ENOX (%)	RR (95% CI)	P Value	BE (%)	ENOX (%)	RR (95% CI)	P Value	BE (%)	ENOX (%)	RR (95% CI)	P Value
Principal safety outcome
Major bleed	0.6	0.7	0.88 (0.44-1.76)	.72	0.7	0.6	1.19 (0.66-2.11)	.56	0.7	0.6	1.19 (0.67-2.12)	.55
Major or CRNM bleed	3.1	1.9	1.64 (1.13-2.37)	.009	3.2	1.7	1.89 (1.38-2.59)	<.001	3.1	1.6	1.97 (1.44-2.68)	<.001

Abbreviations: BE, betrixaban; ENOX, enoxaparin; RR, relative risk; CI, confidence interval; CRNM, clinically relevant nonmajor; ULN, upper limit of normal.

The authors concluded that there was no statistically significant difference between extended VTE prophylaxis (35-42 days) with betrixaban and standard VTE prophylaxis (6-14 days) with enoxaparin in acutely ill medical patients. However, a benefit for betrixaban is shown based on the evidence obtained from exploratory analyses. A limitation of this study was that no P values were provided for any baseline demographics or adverse events. Also, 150 patients in the enoxaparin group were given a renally adjusted enoxaparin dose of 20 mg versus the recommended 30 mg dose for patients with CrCl less than 30 mL/min. Underdosing the enoxaparin patients, while not affecting a large number, could potentially skew results.⁹

Safety and Monitoring

The major adverse events with the use of betrixaban were related to bleeding. When compared to enoxaparin in the APEX trial, there was no significant difference in major bleeding (1.19 [0.67-2.12], P = .55]). However, there was significantly increased CRNM bleeding with betrixaban compared to enoxaparin (2.39 [1.64-3.49], P < .001]).^6,9

Betrixaban is not recommended in pregnancy and should be avoided in patients with hepatic impairment. Dose reductions are recommended in patients with renal impairment.⁶

Like the other DOACs in its class, betrixaban has a black box warning of epidural or spinal hematomas in patients who are receiving neuraxial anesthesia or undergoing spinal puncture. It has also not been studied in patients with prosthetic heart valves and therefore use is not recommended in this population.⁶

Dosage and Administration

Betrixaban is available in both 40 mg and 80 mg capsules. The recommended initial dose is 160 mg on the first day then followed with 80 mg daily for 35 to 42 days. It is recommended to take the medication with food. The initial recommended dose for patients with renal impairment and a creatinine clearance between 15 mL/min to 30 mL/min.⁶ Due to the drug-drug interactions with P-gp inhibitors, it is still recommended to initiate the half dose of 40 mg when patients are concomitantly taking amiodarone, verapamil, or short courses of azithromycin, clarithromycin, and ketoconazole.^6,9,10 It is also recommended to use caution with concurrent use of antiplatelet agents, nonsteroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and avoid other anticoagulants.⁶

Discussion

The APEX trial showed both safety and efficacy of betrixaban for VTE prophylaxis in high-risk patients for up to 42 days. Previous studies investigated other extended duration treatment options such as enoxaparin, rivaroxaban, and apixaban. While efficacious in some patient populations, there was a significantly increased risk of major bleeding that caused safety concerns.¹¹ The Extended Prophylaxis for VTE in Acutely Ill Medical Patient with Prolonged Immobilization (EXCLAIM) study looked at continuing enoxaparin 40 mg for 28 days after discharge. A total of 6085 patients were randomized to receive either enoxaparin or placebo. Like betrixaban, enoxaparin showed efficacy in VTE reduction; however, it was only significantly seen in elderly patients, females, and patients with a higher level of immobilization. There were increased bleeding rates seen in the enoxaparin group as expected and a formal recommendation for extended duration VTE prophylaxis could not be made.¹²

Subsequently, the Apixaban Dosing to Optimize Protection from Thrombus (ADOPT) study looked at utilizing apixaban versus enoxaparin for extended duration VTE prophylaxis. Over 6000 patients were randomized to either receive apixaban 2.5 mg twice daily for 30 days versus enoxaparin 40 mg for 10 to 14 days. Like the APEX trial, ADOPT also excluded AF patients.¹³ Apixaban was not superior to enoxaparin in VTE prevention postdischarge and was associated with more bleeding events compared to enoxaparin. In a noninferiority study, rivaroxaban 10 mg daily for 35 days was compared to enoxaparin in acutely ill medical patients in the MAGELLAN trial.¹⁴ Although it showed to be noninferior to enoxaparin, rivaroxaban had a higher incidence of bleeding compared to enoxaparin. Therefore, both of these trials were not successful in showing efficacy in reducing VTE compared to enoxaparin and also had a higher risk of bleeding. In the APEX trial, the use of 40 mg of betrixaban for patients with renal insufficiency or those on strong P-glycoprotein inhibitors decreased the risk of major bleeding compared to enoxaparin. Also, enrollment of patients with a higher degree of immobility improved its efficacy when compared to enoxaparin.

Currently, there are only parenteral options for acute medically ill patients at high risk for VTE for thromboprophylaxis. The oral route of betrixaban, in combination with its safety profile, makes it an appealing, patient friendly alternative to parenteral enoxaparin giving it a particular niche. There are limitations in use, however. While the phase II EXPLORE-Xa trial included patients with AF and EXPERT included post-orthopedic (knee) surgical patients, it is important to note that those patients were excluded from the APEX trial.^7,8 Unlike like other DOACs, betrixaban cannot be recommended for stroke prevention in AF patients or VTE postsurgical prophylaxis patients. The other DOACs include these indications but are not efficacious and have an increased risk of bleeding and therefore cannot be considered as oral alternatives for VTE prophylaxis in the acute medically ill patients. Additionally, betrixaban’s safety and efficacy has not been evaluated and is not recommended for use in patients with prosthetic heart valves.

Conclusion

Betrixaban is the first DOAC approved for VTE prophylaxis in adult, acutely ill patients at risk for thromboembolisms. The oral route of betrixaban, in combination with its safety profile, makes it an appealing, patient friendly alternative to parenteral enoxaparin giving it a particular niche.